Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome

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Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome

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Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome
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Meteyer, Carol U.
Barber, Daniel
Mandl, Judith N.
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Landes Bioscience
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"White nose syndrome, caused by Geomyces destructans, has killed more than 5 million cave hibernating bats in eastern North America. During hibernation, the lack of inflammatory cell recruitment at the site of fungal infection and erosion is consistent with a temperature-induced inhibition of immune cell trafficking. This immune suppression allows G. destructans to colonize and erode the skin of wings, ears and muzzle of bat hosts unchecked. Yet, paradoxically, within weeks of emergence from hibernation an intense neutrophilic inflammatory response to G. destructans is generated, causing severe pathology that can contribute to death. We hypothesize that the sudden reversal of immune suppression in bats upon the return to euthermia leads to a form of immune reconstitution inflammatory syndrome (IRIS), which was first described in HIV-infected humans with low helper T lymphocyte counts and bacterial or fungal opportunistic infections. IRIS is a paradoxical and rapid worsening of symptoms in immune compromised humans upon restoration of immunity in the face of an ongoing infectious process. In humans with HIV, the restoration of adaptive immunity following suppression of HIV replication with anti-retroviral therapy (ART) can trigger severe immune-mediated tissue damage that can result in death. We propose that the sudden restoration of immune responses in bats infected with G. destructans results in an IRIS-like dysregulated immune response that causes the post-emergent pathology." -- Authors
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Pathologyineuthermicbatswithwhitenosesyndromesuggestsanatural manifestationofimmunereconstitutioninflammatorysyndromeCarolU.Meteyer,1,DanielBarber2andJudithN.Mandl3,*1USGeologicalSurvey;NationalWildlifeHealthCenter;Madison,WIUSA;2TLymphocyteBiologyUnit;LaboratoryofParasiticDiseases;NationalInstituteofAllergy andInfectiousDiseases;NationalInstitutesofHealth;Bethesda,MDUSA;3LymphocyteBiologySection;LaboratoryofSystemsBiology;NationalInstituteofAllergy andInfectiousDiseases;NationalInstitutesofHealth;Bethesda,MDUSACurrentaffiliation:USGeologicalSurveyEnvironmentalHealth;USGSNationalCenter;Reston,VAUSAKeywords: cave-hibernatingbats, Geomycesdestructans ,hibernation-induced immunesuppression,immunecell trafficking,immunereconstitution inflammatorysyndrome(IRIS), Myotis lucifugus ,whitenosesyndrome Abbreviations: ART,anti-retroviral therapy;CD4Tcells,CD4markerpositiveTlymphocytehelpercells; IRIS,immunereconstitution inflammatorysyndrome; LPS,lipopolysaccharide;TNF,tumor necrosisfactor;WNS,white-nose syndrome Submitted:07/19/12 Revised:09/20/12 Accepted:09/21/12 http://dx.doi.org/10.4161/viru.22330*Correspondenceto:JudithN.Mandl; Email:mandlj@niaid.nih.govWhitenosesyndrome,causedby Geomycesdestructans,haskilled morethan5millioncavehibernating batsineasternNorthAmerica.During hibernation,thelackofinflammatorycell recruitmentatthesiteoffungalinfection anderosionisconsistentwithatemperature-inducedinhibitionofimmunecell trafficking.Thisimmunesuppression allows G.destructans tocolonizeand erodetheskinofwings,earsandmuzzle ofbathostsunchecked.Yet,paradoxically,withinweeksofemergencefrom hibernationanintenseneutrophilic inflammatoryresponseto G.destructans isgenerated,causingseverepathology thatcancontributetodeath.Wehypothesizethatthesuddenreversalof immunesuppressioninbatsuponthe returntoeuthermialeadstoaformof immunereconstitutioninflammatory syndrome(IRIS).IRISwasfirstdescribed inHIV-infectedhumanswithlowhelper Tlymphocytecountsandbacterialor fungalopportunisticinfections.IRISisa paradoxicalandrapidworseningof symptomsinimmunecompromised humansuponrestorationofimmunity inthefaceofanongoinginfectious process.InhumanswithHIV,the restorationofadaptiveimmunityfollowingsuppressionofHIVreplicationwith anti-retroviraltherapy(ART)cantrigger severeimmune-mediatedtissuedamage thatcanresultindeath.Weproposethat thesuddenrestorationofimmune responsesinbatsinfectedwith G.destructans resultsinanIRIS-likedysregulated immuneresponsethatcausesthepostemergentpathology. Introduction:WhiteNose SyndromeinBats Mortalityincavehibernatingbatswasfirst documentedlateinwinterof2006 2007 incavesofcentralNewYork.Whitenose syndrome(WNS)wasthenameassignedto thenovelinfectiousdiseasedescribedasthe causeofthedeclinesinhibernatingbat populationsbecauseofthewhitepowdery bloomsseenonthemuzzlesofmany affectedbats.WNShassincespreadto sevenspeciesofhibernatingbatsin17US statesandfourCanadianprovinces,killing anestimatedfivemillionbats.1,2Recently publishedresultsofinfectivitytrialsconfirmedthat G.destructans isthecausative agentofWNS.3Evidencesuggeststhatthis pathogenmayhavebeenintroducedfrom Europewhereinfectionwith G.destructans isnotassociatedwithbatmortality.4-6G. destructans belongstoagenusoforganic decomposers,yetthisfungalinfectionhas causedcatastrophicdeclinesincavehibernatingbatsthatsurpassanyothercutaneous fungalinfectionsofmammalsdocumented todate.Researchtodeterminehowthis fungushasspreadsoquicklyandresultedin suchalargenumberofdeathsisjust beginning.Thebodytemperatureof hibernatingbatsrangesfrom2 15C, whichcloselymatchesoptimaltemperaturesforthegrowthof G.destructans .7-9As PERSPECTIVEVirulence3:7,1 6;November15,2012;G2012LandesBioscience www.landesbioscience.com Virulence 1

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thehibernationseasonprogresses,fungal colonizationanderosionofthewing membranecanbecomesevere,potentially disruptingphysiologicalprocessesthatcontrolwaterandelectrolytebalance,torpor lengthandenergyconservationduring hibernation.10-12Inspiteofextensivecolonizationofwingmembraneby G.destructans duringhibernation,littleappreciable grosspathologyisevident( Fig.1A ).WNS positivebatscollectedfromcavesnearthe endofhibernationandheldincaptivityand providedwithwarmth,foodandwaterhave shownaprogressionofincreasingwing pathologythatbeginsapproximatelythree weekspostarousalandcontinuesfor anotherthreeweeks( Fig.1BandC )until visiblesignsofhealingcanbeseen ( Fig.1D ).13Thusfar,littleattentionhas beendirectedtowardexplainingthelackof effectiveimmuneresponseto G.destructans infectionduringhibernationandprocesses thatcontributetoandcomplicaterecovery afterbatsemergefromhibernation.13ImmunityduringHibernation Likemostothermammalianspecies,batsare homeothermsandmaintaintheirbody temperatureat35 39Catconsiderable energycost.14Hibernationallowssurvival duringwintermonthswhenfoodisunavailableandtemperaturescandropbelow freezing.Duringhibernation,batsentera stateoftorporwheretheirbodytemperature dropstonearambienttemperatureswith intermittentshortperiodsofarousal. Torporisaccompaniedbyreductionsin physicalactivity,metabolicrate,heartrate andrespiratoryrate,aswellasaswitchin metabolismfromcarbohydrate-based(glycolysis)tofatcatabolism.14-16Immune responsesaretemperaturesensitiveand metabolicallycostly17,18andrecentwork suggeststhataspectsofimmunefunction arealsodownregulatedinbatsduring hibernation.18Recentadvancesinmicroscopytoolsthatenablethetrackingof immunecellmovementinlivemice19have revealedtheexquisitetemperaturesensitivityofimmunecellmotilityandfunction; somecelltypes,suchaslymphocytes,may bemoresensitivethanothers(MandlJN, unpublishedresults).20Dataarelackingon Figure1. Oneof30LittleBrownBatswithwhite-nosesyndromecollectedfromhibernationApril13,2010andtakenintorehabilitation.Warmth,food, andwaterwereprovidedandthisbatwasphotographedovertime.PhotographswereusedwithpermissionfromGregoryTurner,MickValentand JackieKashmer.( A )PhotographtakenwithtoplightinginhibernaculaatcollectionApril13,2010.Nogrosslesionscanbeseen,butthedustingofwhite materialonthewingsurfaceisevidenceoffungalinfection.( B )Photographofbat(A)takenonApril29,2010after16dofrehabilitation.The transilluminatedwingwasphotographedoutstretchedoveralightboxandshowsareticularpatternofwingdamage.( C )Photographofbat(A)taken May11,2010showsprogressivelyworseningofwingdamage29dafterbeingtakenintorehabilitation.Lossoftissueisevidentandthewingmembrane isfragile.Inthewild,withoutprovisionoffood,water,andprotection,thisbatwouldbeunlikelytosurvive.( D )Photographofbat(A)takenMay20,2010, wherethereisevidenceofwinghealing9dafterphotograph1Cand38dofrehabilitation. 2 Virulence Volume3Issue7

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regulationofimmunefunctioninhibernating mammalsanditisunclearwhethertheyhave adaptedtoretainspecificimmunefunctions evenatlowbodytemperatures.Traditional batpathogenslikelyreplicatelessefficiently whenthebathostislessmetabolicallyactive andhavereducedtransmissionrateswith reducedhostmobility.Ifthisisthecase,the normalphysiologicalimmunosupressionthat occursinthecontextoftorpormaynot necessarilyrenderhibernatingbatsmore susceptibletotypical,co-evolvedpathogens. Verylittleiscurrentlyknownaboutthe immunesystemofbats,eitherduring hibernationortheireuthermic,activeperiod.16Althoughdatafromstudiesofimmune functionduringhibernationinothermammalsdoexist,itisstillunclearwhichaspects ofimmunityarealteredduringthisdownregulatedstate.20Asearlyasthe1960s, experimentalinfectionsofhibernating groundsquirrelswithColoradotickfever virusshowedthatanimalshadprotracted viremiaandreducedantibodytiterswhen theywereinfectedjustpriortoinductionof torpor.21Morerecentstudiesshowedthat unlikeeuthermicanimals,injectionsofLPS inhibernatinggroundsquirrelsdidnotresult infever.22Whilethisimpliesthatinnate immunecellfunctionisalteredintorpid animals,itremainsunknownwhetherinnate sensingpathways,cytokineproduction,cell recruitmentorotheraspectsofinnate immunecellfunctionareaffected. Furthermore,consistentwithobservedeffects oftemperatureonthe motilityofimmune cells,itisbecomingclearthathibernation resultsinsubstantialchangesinthetraffickingbehaviorofcellsoftheadaptiveimmune system,TandBlymphocytes.Bothin hibernatinggroundsquirrelsandSyrian hamsters,circulatingbloodlymphocyte countsaredramaticallydecreasedcompared witheuthermicanima ls,withBandTcells beingsequesteredinsecondarylymphoid organsatlowbodytemperatures.23,24Similarly,followingtheexperimentalinductionoftorporusing5'AMPinjectedinto mice,25lymphocyteegressfromsecondary lymphoidorgansisgreatlyreduced(Mandl JN,unpublishedresults).Theretentionof lymphocyteswithinsecondarylymphoid organsduringhibernationmaybeameans toensuresurvivalofthisspecializedpopulationofcells.However,sequestrationof lymphocyteswouldalsopreventthemfrom homingtositesofinfectionreducingboth immunesurveillanceandlimitingthegenerationofcellularimmuneresponsesthat playanessentialroleinpathogenclearance. Furtherevidencethatlymphocyteactivation, functionand/orhomingarerestrictedduring torporisthesuccessfulmaintenanceofskin allograftstransplantedduringhibernation whicharesubsequentlyrejectedwhenanimalsreturntoeuthermiaattheendofthe hibernationseason.26BatsinfectedwithWNSduringhibernationnotonlyshownogrossevidenceof pathology,buthistopathologyindicatesthat theinitiationofinflammatoryresponsesand/ ortherecruitmentofimmunecellstositesof G.destructans infectiondoesnotoccurwhen animalsarehibernating( Fig.2AandB ).11,13Theuniquehistologyof G.destructans is diagnosticforbatswithWNSandconsistsof denseaggregatesofrobusthyphaethatforma definedinterfacewithskinanderosionalong theleadingedgeofcontact.11Yet,inspiteof theinvasivenatureof G.destructans ,neutrophilsandmacrophagesarecharacteristicallyabsentfromsitesofpathogeninvasion inhibernatingbatswithWNS( Fig.2B ).11Notonlyisthelowbodytemperatureof hibernatingbatscondu civetothereplication ofthisnovelemergingpathogen,butthe absenceofhistologicallyvisibleinflammatory responsesintheskinsuggeststhat,atleast duringtorpor,thisfungusisnotbeing limitedbyeffectiveimmunecontrol. RoleofImmunopathologyinWNS Ifnaturalimmunesuppressionduring hibernationisakeyaspectofthelackof resistanceofbatstoWNS,thenthereturnto euthermiaandthereestablishmentofimmunocompetenceshouldallowbatstomount effectiveimmuneresponsesthatclearthe infection.Restorationofimmunityin hibernatinganimalsfollowingarousalfrom torporhaspresumablyevolvedtoberapidto preventincreasedsusceptibilitytotraditional activepathogensina euthermicworld. Indeed,bloodlymphocytecountsreturnto normallevelswithinhoursoftheestablishmentofnormalmetabolicactivityinground squirrels.24Yet,paradoxically,therestoration ofimmunityinbatsfollowingarousalmay actuallycontributetoasubstantialworsening ofWNSpathologyinaffectedbats.Weeks afteremergencefromhibernation,batscan befoundmoribundandunabletofly,or dead.Thesebats,aswellasbatsobservedin rehabilitation,havevisiblepathologyofwing membrane( Figs.1and2C ).Whilewingsof infectedbatsoftenlooknormalduring hibernation( Figs.1Aand2A )andinfection canonlybeidentifiedmicroscopically ( Fig.2B ),overtwingdamageappearswithin weeksofeuthermiaconcomitantwithhistologicevidenceofinflammation( Fig.2C F).13Thepost-emergentbatshadintense neutrophilicinflamma tionassociatedwith invasive G.destructans ;inflammationthatis characteristicallyabsentintorpidanimals.11Arecentexampleofthiswasasubmissionof ninefemaleLittleBrownBatstotheUS GeologicalSurvey sNationalWildlifeHealth Center.Thesebatswerefounddistantfrom winteringhibernationsitesinAprilandMay onanislandoffofthecoastofMaine;their wingsweredamagedandtheywereunableto fly.Wingmembranesweredry,stiff,fragile andcontractedwithlossofelasticity ( Fig.2C ).Inspiteofeagerlyeatingthefood andwaterprovidedduringrehabilitation, thesebatsdiedwithin30h(AnnRivers, personalcommunication).WinghistopathologyoftheninebatsfromMainealsohad multifocallyintenseneutrophilinfiltration withareasofassociatedacutenecrosisand edema( Fig.2D )andregionsofdense degeneratingneutrophilaggregation ( Figs.2DandE )Thisrapidrestorationof theinflammatoryresponseandmobilization ofinflammatorycellswithassociatedwing damageafterhibernationistypicalofwhat hasbeenseeninWNSpositivebatstwoto threeweeksaftertheyhavebecome euthermic( Figs.1and2C E ). WesuspectthatthispathologyinNorth Americanbatsthatbecomeeuthermic whileinfectedwith G.destructans isdue toaphenomenondocumentedinhumans calledimmunereconstitutioninflammatorysyndrome(IRIS).IRISwasfirst documentedinHIVpositivehumanscoinfectedwithopportunisticpathogensand treatedwithantiretroviraltherapy.27-30ImmuneReconstitution InflammatorySyndrome inHumansFollowingReversal ofImmunosuppression DuringHIVinfection,immunosuppressionoccursasaconsequenceofthe www.landesbioscience.com Virulence 3

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Figure2. ( A )LittleBrownBatfoundFebruary8,2009frozenoutsideofthesmallopeningofacoppermine.Thetransilluminatedwingwas photographedoutstretchedoveralightboxandshowsnoevidenceofwingdamage.( B )PeriodicacidSchiffstainedsectionofwingmembranefrombat (2A)showscharacteristicdenseaggregatesofrobusthyphaeformingadefinedinterfacewiththeskin,erosionalongthebroadzoneofskincontact (arrows)andnovisibleinflammatoryresponse.( C)OneofnineLittleBrown.NinebatswerefoundonthegroundandunabletoflybetweenApril4and May7,2012.ThisbatwascollectedApril4,takenintorehabilitation,ateanddrank,butdiedwithin18hofarrival.Thewingwasphotographed outstretchedoveralightboxandvisibledamagecanbeseenwithdarkareasofcontractionandlossofelasticity.( D )PeriodicacidSchiffstainedsection ofwingmembranefromthebatin Figure2C .Severeneutrophilicinflammationandedema(bracket)inresponsetofungalhyphae(arrow).( E )Different fieldfromsameslideasin Figure2D showsathicklayerofdegeneratingneutrophils(brackets)atthemarginsofadenseaggregateoffungalhyphae erodingepidermis(arrow).( F )LittleBrownBatin Figure2C .Degeneratingneutrophils(arrowheads)surroundthedenseaggregateoffungalhyphae (arrows). 4 Virulence Volume3Issue7

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depletionofCD4Tcells,acriticalimmune cellpopulationoftheadaptiveimmune system.TheHIV-inducedlossofCD4T cellsresultsinhostsusceptibilitytomany opportunisticinfectionsandtherecoveryof CD4Tcellfunctionfollowingtreatment withantiretroviraltherapyusuallyrestores resistancetothesemicrobialinfections.31However,withinafewweeksafterstarting antiretroviraltherapy,someAIDSpatients undergoarapiddeteriorationinsymptoms ratherthantheexpectedclinicalimprovement.Thisparadoxicaladverseeventof antiretroviraltherapy,IRIS,occursmost frequentlyinpatientswhoareseverelyCD4 TcelldeficientandharboramicrobialcoinfectionatthetimeofARTinitiation.29,32,33Interestingly,IRISalsotends tooccurinindividualswiththebestand mostrapidresponsetoART,asmeasured bythedecreaseinHIVviralloads,andwith asuddenincreaseinCD4Tcellnumbers. IRIShasbeendocumentedinpatientswith adiversearrayofco-infections,andthe manifestationofdiseasedependsonthe particularopportunisticpathogenandthe siteofinfection.Fungalinfectionsin particularareoftenassociatedwithHIVIRISevents,andmeningealinfectionwith Cryptococcusneoformans inHIVpositive individualstreatedwithantiretroviraltherapyresultsinthemostlethalformofIRIS. ThemechanismsofHIV-IRISarenot wellunderstood,33buttheprevailing hypothesissuggeststhatwhenHIVviral replicationisinhibitedbyART,the ensuingrecoveryofCD4Tcellsdrives anover-exuberantdestructiveimmune responseagainsttheunderlyingmicrobial co-infectionwithsubsequentdamageto infectedtissue.Datafromarecently developedmodelofexperimentally inducedmycobacterialIRISsupportthe ideathatalthoughCD4Tcellsare normallyrequiredforcontrolofmycobacterialinfections,theycanalsomediate damagingresponsesduringIRIS.34Ithas beenshownthatbothwild-typeandTcell deficientmiceareabletosurvivewith disseminated M.avium infectionformany months.However,whenTcelldeficient miceharboringanestablished M.avium infectionareinjectedwithpurifiedCD4T cells,themicedevelopasevereinflammatorydiseaseanddiewithin1to3weeks afterTcelltransfer.34Thisadoptive transferofCD4Tcellsdoesnotleadto inflammatorydiseasein M.avium infected micethathavenormalnumbersof circulatingTcellsorinTcelldeficient micewithout M.avium infection.This basicobservationillustratesthefundamentalimmunologicalphenomenaof IRIS:onceamicrobialinfectionisestablishedinanimmunodeficienthost, immunerecoverycanbemoredetrimental tothehostthantheopportunisticinfectionitself,atleastintheshort-term. IRISalsooccursfollowingrecovery fromotherformsofimmunosuppression.27-30Forexample,tumornecrosis factor(TNF)blockadeforthetreatment ofrheumatoidarthritisorCrohndisease canincreasesusceptibilityto M.tuberculosis infection,butrapidremovalofTNF blockingdrugsafter M.tuberculosis infectionisestablishedinthesepatientscan furtherexacerbatethepathology.35In somemultiplesclerosispatientswhoare treatedwiththeintegrinblockingdrug natalizumabtopreventlymphocytemigrationintotheCNS,aquiescentinfection withJCpolyomavirusmayreactivate, leadingtoprogressivemultifocalleukoencephalopathy.Rapidremovaloftheintegrinblockingdrugcanleadtosevere worseningofCNSinflammationasthe lymphocytesrushbackintothebrainin responsetoboththemultiplesclerosisand JCpolyomavirusreplication.36,37Asafinal example,patientswithhematologicmalignancieswhoreceivechemotherapytokill themalignanthematopoieticcellsinthe bonemarrowcandevelopprogressive aspergillosisasaresultoftheresulting neutropenia,butrecoveryofneutrophil numbersissometimesassociatedwitha worseningofpulmonaryradiologicalfindingsandclinicalsymptomsdespitesignsof effectiveantifungaldrugtreatment.38WNSasaFormofIRIS Collectively,HIV-IRISandotherexamples ofIRISthatarecausedbyadetrimental outcomeoftreatmentwithimmunosuppressivetherapies,demonstratethatIRIS resultsfromacycleofimmunosuppression, outgrowthofanopportunisticmicrobial infectionandsuddenrestorationofimmune function.Thisdiseasecourseisdirectly paralleledinWNSandweproposethat thepathologyofWNSisaformofIRISakin towhatoccursinhumans.Inhibernating speciesthathavebeenstudied,20thecold corebodytemperaturesreachedduring hibernationresultinimmunesuppression. Histologicevidencesuggeststhatthisdownregulationofimmunityalsooccursin hibernatingbats,11,13enablingtheunabated growthofthecold-loving G.destructans and leadingtothedevelopmentofprogressive fungalinfectiononthemuzzleandglabrous surfacesoftheirbody.Oncethebatsbecome euthermicandbodytemperaturesreturnto normal,immunefunctionisquicklyreestablished.Atthispoint,thereanimated populationsofimmunecellssuddenly encounterthefungalinfectionwhichprogressedinseverityduringhibernation.The resultingresponseisanexuberantmobilizationofneutrophilstothesitesoffungal infection,13resultinginnecrosiswithedema ( Fig.2D )andsequesteringoffungalhyphae innetworksofdegenerativecellmaterial resemblingneutrophilextracellulartraps ( Fig.2EandF ).39AswithIRISinhumans, theintensityandextentoftissueinfection determinesiftheexuberantinflammatory responseassociatedwithrapidreconstitution ofimmunitywillcauseseveretissuedamage anddeath,oreliminatethepathogenand resultinhostrecovery. ConclusionsandImplications Wehypothesizethataperfectstormof pathogenandhostfactorsleadstoIRISin newlypost-hibernalemergenteuthermic batswithWNSandthatthisisakey determinantofpathologyinWNSpositive batsthathavesurvivedthehibernation period.Thusfar,theoccurrenceofIRIShas onlybeenassociatedwithpharmaceutical interventionsininfectedhumansand experimentallyinducedinmice.However, similaritiesinthecourseofdiseaseinbats withWNSsuggeststhattheabsenceofan immuneresponseto G.destructans during torporenablesuncontrolledinfectionwith G.destructans atlowhibernationbody temperaturesandthesubsequentrapid reversalofhibernation-inducedimmune suppressionwhenthebatsbecomeeuthermic,leadstoafulminateinflammatory responseandconsequentimmunemediatedtissuedestruction.Immunologicalstudiesofbatsduringhibernation, www.landesbioscience.com Virulence 5

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euthermiaandintheperiodwhereimmunityisreestablishedattheendofhibernation arecriticaltounderstandinghowthese naturalimmunologicstatesinfluence pathogenvirulence,recoveryandsurvival ofbatswithWNS.AcknowledgmentsAuthorsaregratefultoGregoryTurner (PennsylvaniaGameCommission),Mick Valent(NewJerseyDivisionofFishandWildlife)andJackieKashmer(NewJerseyBatSanctuary)forpermissiontousethephotographsin Figure1andAnneRivers(AcadiaWildlife Foundation)forsubmittingtheLittleBrown BatsfromMaine.Diagnosticworkwasfunded bytheUS.GeologicalSurvey.Useoftradeor productnamesdoesnotimplyendorsement bytheUSgovernment.References1.USFishandWildlifeService.NorthAmericanbatdeath tollexceeds5.5millionfromwhite-nosesyndrome.:http:// www.fws.gov/WhiteNoseSyndrome/index.html,2012. 2.ZimmermanR.Ecology.Biologistsstruggletosolvebat deaths.Science2009;324:1134-5;PMID:19478160; http://dx.doi.org/10.1126/science.324_1134 3.LorchJM,MeteyerCU,BehrMJ,BoylesJG,Cryan PM,HicksAC,etal.Experimentalinfectionofbats withGeomycesdestructanscauseswhite-nosesyndrome.Nature2011;480:376-8;PMID:22031324; http://dx.doi.org/10.1038/nature10590 4.PuechmailleSJ,VerdeyrouxP,FullerH,GouilhMA, BekaertM,TeelingEC.White-nosesyndromefungus (Geomycesdestructans)inbat,France.EmergInfect Dis2010;16:290-3;PMID:20113562;http://dx.doi. org/10.3201/eid1602.091391 5.WarneckeL,TurnerJM,BollingerTK,LorchJM, MisraV,CryanPM,etal.Inoculationofbatswith EuropeanGeomycesdestructanssupportsthenovel pathogenhypothesisfortheoriginofwhite-nose syndrome.ProcNatlAcadSciUSA2012;109: 6999-7003;PMID:22493237;http://dx.doi.org/10. 1073/pnas.1200374109 6.WibbeltG,KurthA,HellmannD,WeishaarM, BarlowA,VeithM,etal.White-nosesyndromefungus (Geomycesdestructans)inbats,Europe.EmergInfect Dis2010;16:1237-43;PMID:20678317;http://dx. doi.org/10.3201/eid1608.100002 7.BlehertDS,LorchJM,BallmannAE,CryanPM, MeteyerCU.BatWhite-nosesyndromeinNorth America.Microbe2011;6:267-73. 8.GargasA,TrestMT,ChristensenM,VolkTJ,Blehert DS. Geomycesdestructans sp.nov.associatedwithbat white-nosesyndrome.Mycotaxon2009;108:147-54; http://dx.doi.org/10.5248/108.147 9.ChaturvediV,SpringerDJ,BehrMJ,RamaniR,LiX, PeckMK,etal.MorphologicalandmolecularcharacterizationsofpsychrophilicfungusGeomycesdestructans fromNewYorkbatswithWhiteNoseSyndrome (WNS).PLoSOne2010;5:e10783;PMID:20520731; http://dx.doi.org/10.1371/journal.pone.0010783 10.CryanPM,MeteyerCU,BoylesJG,BlehertDS.Wing pathologyofwhite-nosesyndromeinbatssuggestslifethreateningdisruptionofphysiology.BMCBiol2010; 8:135;PMID:21070683;http://dx.doi.org/10.1186/ 1741-7007-8-135 11.MeteyerCU,BucklesEL,BlehertDS,HicksAC, GreenDE,Shearn-BochslerV,etal.Histopathologic criteriatoconfirmwhite-nosesyndromeinbats.JVet DiagnInvest2009;21:411-4;PMID:19564488; http://dx.doi.org/10.1177/104063870902100401 12.ReederDM,FrankCL,TurnerGG,MeteyerCU, KurtaA,BritzkeER,etal.Frequentarousalfrom hibernationlinkedtoseverityofinfectionandmortality inbatswithwhite-nosesyndrome.PLoSOne2012;7: e38920;PMID:22745688;http://dx.doi.org/10.1371/ journal.pone.0038920 13.MeteyerCU,ValentM,KashmerJ,BucklesEL,Lorch JM,BlehertDS,etal.Recoveryoflittlebrownbats (Myotislucifugus)fromnaturalinfectionwith Geomycesdestructans,white-nosesyndrome.JWildl Dis2011;47:618-26;PMID:21719826 14.NeuweilerG.TheBiologyofBats.NewYork:Oxford UniversityPress,2000:68-76. 15.MelvinRG,AndrewsMT.Torporinductionin mammals:recentdiscoveriesfuelingnewideas.Trends EndocrinolMetab2009;20:490-8;PMID:19864159; http://dx.doi.org/10.1016/j.tem.2009.09.005 16.CareyHV,AndrewsMT,MartinSL.Mammalian hibernation:cellularandmolecularresponsesto depressedmetabolismandlowtemperature.Physiol Rev2003;83:1153-81;PMID:14506303 17.LochmillerRL,DeerenbergC.Trade-offsinevolutionaryimmunology:justwhatisthecostofimmunity? Oikos2000;88:87-98;http://dx.doi.org/10.1034/j. 1600-0706.2000.880110.x 18.MooreMS,ReichardJD,MurthaTD,ZahediB,Fallier RM,KunzTH.Specificalterationsincomplement proteinactivityoflittlebrownmyotis(Myotislucifugus) hibernatinginwhite-nosesyndromeaffectedsites.PLoS One2011;6:e27430;PMID:22140440;http://dx.doi. org/10.1371/journal.pone.0027430 19.GermainRN,MillerMJ,DustinML,NussenzweigMC. Dynamicimagingoftheimmunesystem:progress,pitfalls andpromise.NatRevImmunol2006;6:497-507; PMID:16799470;http://dx.doi.org/10.1038/nri1884 20.BoumaHR,CareyHV,KroeseFG.Hibernation:the immunesystematrest?JLeukocBiol2010;88:619-24; PMID:20519639;http://dx.doi.org/10.1189/jlb.0310174 21.EmmonsRW.Coloradotickfever:prolongedviremia inhibernatingCitelluslateralis.AmJTropMedHyg 1966;15:428-33;PMID:5938437 22.PrendergastBJ,FreemanDA,ZuckerI,NelsonRJ. Periodicarousalfromhibernationisnecessaryfor initiationofimmuneresponsesingroundsquirrels.Am JPhysiolRegulIntegrCompPhysiol2002;282: R1054-62;PMID:11893609 23.BoumaHR,KroeseFG,KokJW,TalaeiF,Boerema AS,HerwigA,etal.Lowbodytemperaturegovernsthe declineofcirculatinglymphocytesduringhibernation throughsphingosine-1-phosphate.ProcNatlAcadSci USA2011;108:2052-7;PMID:21245336;http://dx. doi.org/10.1073/pnas.1008823108 24.BoumaHR,StrijkstraAM,BoeremaAS,DeelmanLE, EpemaAH,HutRA,etal.Bloodcelldynamicsduring hibernationintheEuropeanGroundSquirrel.VetImmunol Immunopathol2010;136:319-23;PMID:20399508; http://dx.doi.org/10.1016/j.vetimm.2010.03.016 25.ZhangJ,KaasikK,BlackburnMR,LeeCC.Constant darknessisacircadianmetabolicsignalinmammals. Nature2006;439:340-3;PMID:16421573;http://dx. doi.org/10.1038/nature04368 26.ShivatchevaTM.SurvivalofskinallograftsinEuropean groundsquirrels,SpermophiluscitellusL.,during hibernation.FoliaBiol(Krakow)1988;36:213-21; PMID:3069502 27.SunHY,SinghN.Immunereconstitutioninflammatorysyndromeinnon-HIVimmunocompromised patients.CurrOpinInfectDis2009;22:394-402; PMID:19483618;http://dx.doi.org/10.1097/QCO. 0b013e32832d7aff 28.GuptaAO,SinghN.Immunereconstitutionsyndrome andfungalinfections.CurrOpinInfectDis2011;24: 527-33;PMID:22025021;http://dx.doi.org/10.1097/ QCO.0b013e32834ab20a 29.BarberDL,AndradeBB,SeretiI,SherA.Immune reconstitutioninflammatorysyndrome:thetrouble withimmunitywhenyouhadnone.NatRev Microbiol2012;10:150-6;PMID:22230950 30.SinghN,PerfectJR.Immunereconstitutionsyndrome associatedwithopportunisticmycoses.LancetInfect Dis2007;7:395-401;PMID:17521592;http://dx.doi. org/10.1016/S1473-3099(07)70085-3 31.GrossmanZ,Meier-SchellersheimM,PaulWE,Picker LJ.PathogenesisofHIVinfection:whatthevirus sparesisasimportantaswhatitdestroys.NatMed 2006;12:289-95;PMID:16520776;http://dx.doi.org/ 10.1038/nm1380 32.ShelburneSA,3rd,HamillRJ,Rodriguez-Barradas MC,GreenbergSB,AtmarRL,MusherDW,etal. Immunereconstitutioninflammatorysyndrome:emergenceofauniquesyndromeduringhighlyactive antiretroviraltherapy.Medicine(Baltimore)2002;81: 213-27;PMID:11997718;http://dx.doi.org/10.1097/ 00005792-200205000-00005 33.ShelburneSA,MontesM,HamillRJ.Immune reconstitutioninflammatorysyndrome:moreanswers, morequestions.JAntimicrobChemother2006;57: 167-70;PMID:16354748;http://dx.doi.org/10.1093/ jac/dki444 34.BarberDL,Mayer-BarberKD,AntonelliLR,Wilson MS,WhiteS,CasparP,etal.Th1-drivenimmune reconstitutiondiseaseinMycobacteriumaviuminfectedmice.Blood2010;116:3485-93;PMID: 20656932;http://dx.doi.org/10.1182/blood-2010-05286336 35.RivoisyC,AmroucheL,CarcelainG,SrniD, BourgaritA.Paradoxicalexacerbationoftuberculosis afterTNF a antagonistdiscontinuation:bewareof immunereconstitutioninflammatorysyndrome.Joint BoneSpine2011;78:312-5;PMID:21334948;http:// dx.doi.org/10.1016/j.jbspin.2011.01.003 36.JohnsonT,NathA.Immunereconstitutioninflammatorysyndromeandthecentralnervoussystem.Curr OpinNeurol2011;24:284-90;PMID:21499099; http://dx.doi.org/10.1097/WCO.0b013e328346be57 37.MiravalleA,JensenR,KinkelRP.Immunereconstitutioninflammatorysyndromeinpatientswithmultiple sclerosisfollowingcessationofnatalizumabtherapy. ArchNeurol2011;68:186-91;PMID:20937940; http://dx.doi.org/10.1001/archneurol.2010.257 38.MiceliMH,MaertensJ,BuvK,GrazziuttiM,Woods G,RahmanM,etal.Immunereconstitutioninflammatorysyndromeincancerpatientswithpulmonary aspergillosisrecoveringfromneutropenia:Proofof principle,description,andclinicalandresearchimplications.Cancer2007;110:112-20;PMID:17525971; http://dx.doi.org/10.1002/cncr.22738 39.FuchsTA,AbedU,GoosmannC,HurwitzR,Schulze I,WahnV,etal.Novelcelldeathprogramleadsto neutrophilextracellulartraps.JCellBiol2007;176: 231-41;PMID:17210947;http://dx.doi.org/10.1083/ jcb.200606027 6 Virulence Volume3Issue7


Description
"White nose syndrome,
caused by Geomyces destructans, has killed more than 5 million
cave hibernating bats in eastern North America. During
hibernation, the lack of inflammatory cell recruitment at the
site of fungal infection and erosion is consistent with a
temperature-induced inhibition of immune cell trafficking. This
immune suppression allows G. destructans to colonize and erode
the skin of wings, ears and muzzle of bat hosts unchecked. Yet,
paradoxically, within weeks of emergence from hibernation an
intense neutrophilic inflammatory response to G. destructans is
generated, causing severe pathology that can contribute to
death. We hypothesize that the sudden reversal of immune
suppression in bats upon the return to euthermia leads to a
form of immune reconstitution inflammatory syndrome (IRIS),
which was first described in HIV-infected humans with low
helper T lymphocyte counts and bacterial or fungal
opportunistic infections. IRIS is a paradoxical and rapid
worsening of symptoms in immune compromised humans upon
restoration of immunity in the face of an ongoing infectious
process. In humans with HIV, the restoration of adaptive
immunity following suppression of HIV replication with
anti-retroviral therapy (ART) can trigger severe
immune-mediated tissue damage that can result in death. We
propose that the sudden restoration of immune responses in bats
infected with G. destructans results in an IRIS-like
dysregulated immune response that causes the post-emergent
pathology." --
Authors


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